Project 4 consists of three clinical protocols. Protocol 1 is an assessment of two new murine retroviral vectors to transduce the HSC of patients with adenosine deaminase (ADA) deficiency. The two second generation vectors both contain promoters, which based upon pre-clinical data, will support ADA gene expression in resting peripheral blood T lymphocytes, the major problem that we have identified in our previous ADA clinical gene therapy trial. Both bone marrow and cord blood HSC will be transduced. Protocol 2 will evaluate patients with common gamma chain (X-linked SCID) deficiency with a MND containing retroviral based vector using HSC of either bone marrow or cord blood origin. The lack of alternative enzyme replacement therapy will permit the evaluation of HSC transduction and a selective advantage for T lymphoid and NK progeny within 3-6 months. Protocol 3 is an evaluation of the capacity of FACS purified bone marrow HSC (CD34+, CD38-, gamma/c) to lymphohematopoietically reconstitute patients who have received myeloablative doses of irradiation. After successful reconstitution with the purified HSC, we will evaluate the ability of lentivirus based vectors to transduce HSC and the clonality of post-transplant lymphohematopoiesis. The three Protocols utilize improved transduction conditions and vectors derived from prior SCOR supported research. It is anticipated that additional clinical protocols and modifications based upon ongoing pre-clinical research will occur during the next SCOR funding period.